@article{3cc2f84c3fa443c7864a6acb08a6da5c,
title = "Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy",
abstract = "Vascular mechanisms of Alzheimer{\textquoteright}s disease (AD) may constitute a therapeutically addressable biological pathway underlying dementia. We previously demonstrated that soluble pathogenic forms of tau (tau oligomers) accumulate in brain microvasculature of AD and other tauopathies, including prominently in microvascular endothelial cells. Here we show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy and drives AD-like brain microvascular deficits. Microvascular impairments in P301S(PS19) mice were partially negated by selective removal of pathogenic soluble tau aggregates from brain. We found that similar to trans-neuronal transmission of pathogenic forms of tau, soluble tau aggregates are internalized by brain microvascular endothelial cells in a heparin-sensitive manner and induce microtubule destabilization, block endothelial nitric oxide synthase (eNOS) activation, and potently induce endothelial cell senescence that was recapitulated in vivo in microvasculature of P301S(PS19) mice. Our studies suggest that soluble pathogenic tau aggregates mediate AD-like brain microvascular deficits in a mouse model of tauopathy, which may arise from endothelial cell senescence and eNOS dysfunction triggered by internalization of soluble tau aggregates.",
author = "Hussong, {Stacy A.} and Banh, {Andy Q.} and {Van Skike}, {Candice E.} and Dorigatti, {Angela O.} and Hernandez, {Stephen F.} and Hart, {Matthew J.} and Beatriz Ferran and Haneen Makhlouf and Maria Gaczynska and Osmulski, {Pawel A.} and McAllen, {Salome A.} and Dineley, {Kelly T.} and Zoltan Ungvari and Perez, {Viviana I.} and Rakez Kayed and Veronica Galvan",
note = "Funding Information: These studies were supported by NIA 1RF1AG057964 to V.I.P. and V.G., NIA 1RF1AG068283 to V.G. and V.I.P., Merit Review Award I01 BX002211-01A2 from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the Robert L. Bailey and daughter Lisa K. Bailey Alzheimer{\textquoteright}s Fund in memory of Jo Nell Bailey to V.G., a William & Ella Owens Medical Research Foundation Grant, the San Antonio Medical Foundation, and the JMR Barker Foundation to V.G. These studies were also supported by an award to V.G. through the NCATS/NIH Clinical and Translational Science Award grant UL1TR002645, and by the Oklahoma Nathan Shock Center of Excellence in the Basic Biology of Aging (NIA P30AG050911), the Cellular and Molecular Geroscience Center of Biomedical Research Excellence (P20GM125528), and the Geroscience Training Program in Oklahoma (T32AG052363). We gratefully acknowledge the support of the NIH NCATS through Grant UL1TR001120, and of the Cancer Prevention and Research Institute of Texas Award RP160844 to the Center for Innovative Drug Discovery. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. These studies used the services of the San Antonio Nathan Shock Center of Excellence in the Biology of Aging (NIH/NIA 2 P30 AG013319-21). S.A.H. was supported by a Career Development Award (1 IK2 BX003798-01A1) from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service. C.V.S. and A.B.O. were supported by NIA Training Grant T32AG021890. C.V.S. was also supported by Alzheimer{\textquoteright}s Association AARF-17-504221. M.J.H. was supported by NCATS/NIH UL1TR001120. V.I.P. was supported by NIA/NIH R03AG052394, NIA/NIH R01AG057964, and the American Federation for Aging Research (AFAR). K.T.D. was supported by NIH/NINDS R01 NS094557. Z.U. is supported by the National Institute on Aging (R01-AG055395, R01-AG047879; R01-AG038747) and the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218, R01-NS100782). R.K. and S.A.M. were supported by R01AG054025, RF1AG055771, and the American Heart Association. AQB was supported by NIH/NIA 1F31AG067732-01 and NIH T32GM113896 (STX-MSTP). We gratefully acknowledge Dr. Nataliya Smith for helpful contributions. Funding Information: These studies were supported by NIA 1RF1AG057964 to V.I.P. and V.G., NIA 1RF1AG068283 to V.G. and V.I.P., Merit Review Award I01 BX002211-01A2 from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the Robert L. Bailey and daughter Lisa K. Bailey Alzheimer{\textquoteright}s Fund in memory of Jo Nell Bailey to V.G., a William & Ella Owens Medical Research Foundation Grant, the San Antonio Medical Foundation, and the JMR Barker Foundation to V.G. These studies were also supported by an award to V.G. through the NCATS/NIH Clinical and Translational Science Award grant UL1TR002645, and by the Oklahoma Nathan Shock Center of Excellence in the Basic Biology of Aging (NIA P30AG050911), the Cellular and Molecular Geroscience Center of Biomedical Research Excellence (P20GM125528), and the Geroscience Training Program in Oklahoma (T32AG052363). We gratefully acknowledge the support of the NIH NCATS through Grant UL1TR001120, and of the Cancer Prevention and Research Institute of Texas Award RP160844 to the Center for Innovative Drug Discovery. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. These studies used the services of the San Antonio Nathan Shock Center of Excellence in the Biology of Aging (NIH/NIA 2 P30 AG013319-21). S.A.H. was supported by a Career Development Award (1 IK2 BX003798-01A1) from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service. C.V.S. and A.B.O. were supported by NIA Training Grant T32AG021890. C.V.S. was also supported by Alzheimer{\textquoteright}s Association AARF-17-504221. M.J.H. was supported by NCATS/NIH UL1TR001120. V.I.P. was supported by NIA/NIH R03AG052394, NIA/NIH R01AG057964, and the American Federation for Aging Research (AFAR). K.T.D. was supported by NIH/NINDS R01 NS094557. Z.U. is supported by the National Institute on Aging (R01-AG055395, R01-AG047879; R01-AG038747) and the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218, R01-NS100782). R.K. and S.A.M. were supported by R01AG054025, RF1AG055771, and the American Heart Association. AQB was supported by NIH/NIA 1F31AG067732-01 and NIH T32GM113896 (STX-MSTP). We gratefully acknowledge Dr. Nataliya Smith for helpful contributions. Publisher Copyright: {\textcopyright} 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
year = "2023",
month = dec,
doi = "10.1038/s41467-023-37840-y",
language = "English (US)",
volume = "14",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}